The taxane family of terpenes, of which baccatin III and Taxol® are members, has been the subject of considerable interest in both the biological and chemical arts. Paclitaxel (Taxol®), a cytotoxic natural product, and docetaxel (Taxotere®), a semi-synthetic derivative, are widely used in the treatment of cancer, E. Baloglu and D. G. I. Kingston, J. Nat. Prod. 62: 1448-1472 (1999). Paclitaxel and docetaxel have the following structures:

Taxanes are mitotic spindle poisons that inhibit the depolymerization of tubulin, resulting in cell death. While docetaxel and paclitaxel are useful agents in the treatment of cancer, their antitumor activity is limited because of 1) lack of selectivity, 2) poor water solubility, 3) no oral bioavailability, 4) inability to cross the blood-brain-barrier (BBB) and 5) occurrence of drug resistance. Some of these limitations can be at least partially explained with the fact that paclitaxel is a good substrate for P-glycoprotein (Pgp). It has been reported that Pgp is over-expressed (mdr1 gene) in multi-drug resistant (MDR) cancer cells, which binds to cytotoxic (antitumor) agents and pumps them out.
Accordingly, there is a need to develop taxane derivatives that are not substrates for the Pgp expressed in the BBB and have improved efficacy, oral bioavailability and improved drug resistance.